Peanut allergy is one of the most common and serious of the immediate hypersensitivity reactions to foods in terms of persistence and severity of reaction. In fact, this allergy is estimated to be involved in the majority of fatal and near-fatal food-related anaphylaxis in all age groups. The prevalence of this allergy has doubled in the last decade and it now affects between 0.6% and 1.2% of the general population. Sicherer et al., Prevalence of the peanut and tree nut allergy in the United States determined by means of random digit dial telephone survey: a 5-year follow-up study, 112(6) J. ALLERGY CLIN. IMMUNOL. 1203, 1203-07 (2003).
This allergy tends to present early in life and only 20% of allergic children become tolerant to peanut. Skolnick et al., The natural history of peanut allergy, 107(2) J. ALLERGY CLIN. IMMUNOL. 367, 367-74 (2001). Sensitization generally occurs in the gastrointestinal tract but can also occur as a consequence of direct or cross-sensitization by inhalation exposure to peanut or cross-reactive environmental antigens such as pollen.
The allergic reaction provoked by peanuts is strictly an IgE mediated type I hypersensitivity reaction. The IgE-allergen complex causes mast cell receptors to cross-link inducing a signal transduction cascade that ends in degranulation and release of a variety of mediators that give rise to the clinical symptoms of peanut hypersensitivity.
The major peanut allergens are seed storage proteins. Although 9 peanut allergens, namely Ara h 1 to Ara h 9, have been reported, Ara h 1, Ara h 2, and Ara h 3 are classified as the major peanut allergens because they are generally recognized by more than 50% of peanut-allergic patients. Burks et al., Identification and characterization of a second major peanut allergen, Ara h II, with use of the sera of patients with atopic dermatitis and positive peanut challenge, 90 J. ALLERGY CLIN. IMMUNOL. 962, 962-69 (1992); Burks et al., Identification of a major peanut allergen, Ara h I, in patients with atopic dermatitis and positive peanut challenges, 88 J. ALLERGY CLIN. IMMUNOL. 172, 172-79 (1991) ; Rabjohn et al., Molecular cloning and epitope analysis of the peanut allergen Ara h 3, 103 J. CLIN. INVEST. 535, 535-42 (1999); Koppelman et al., Purification and immunoglobulin E-binding properties of peanut allergen Ara h 6: evidence for cross-reactivity with Ara h 2, 35(4) CLIN. EXP. ALLERGY 490, 490-97 (2005); Koppelman et al., Quantification of major peanut allergens Ara h 1 and Ara h 2 in the peanut varieties Runner, Spanish, Virginia, and Valencia, bred in different parts of the world, 56(2) ALLERGY 132, 132-37 (2001); Mittag et al., Ara h 8, a Bet v 1-homologous allergen from peanut, is a major allergen in patients with combined birch pollen and peanut allergy, 114 J. ALLERGY CLIN. IMMUNOL. 1410, 1410-17 (2004); Becker et al., Four novel recombinant peanut allergens: more information, more problems, 124 INT. ARCH. ALLERGY IMMUNOL. 100, 100-02 (2001); Lauer et al., Abstracts of the XXVII EAACI Congress of the European Academy of Allergology and Clinical Immunology, 63(88) ALLERGY 158, 158-611 (2008).
Preventive treatment of this allergy consists of avoidance, which is very difficult because of the widespread and often disguised use of peanuts in the food industry. Current pharmacotherapies (antihistamines and corticosteroids) can be used to reduce the symptoms of allergic disease but do not prevent allergic reaction.
Immunotherapy is the only available treatment that can modify the natural course of the allergic disease, by reducing sensitivity to allergens. For immunotherapy, a dose of an allergen is given in order to progressively induce an immune response characterized by tolerance to the antigen/allergen, also known as desensitization. This method is particularly indicated for patients with severe allergic IgE-dependent reactions.
Even though immunotherapy has been in practice for more than 90 years, the exact mechanism of its action is still not clear. In humans, it involves (i) an increase of IgG, in particular IgG4 which is a blocking antibody that may block IgE mediated mechanisms by inhibiting the release of inflammatory mediators from mast cells and basophils, (ii) an increase of regulatory T cells (Treg) leading to a better balance of the Th2/Th1 profile, and (iii) the production of T cells producing IL-10, also known as human cytokine synthesis inhibitory factor (CSIF), which counteracts the inflammatory effect of mast cells and promotes the production of IgG4.
Until now, the immunotherapy could be administered by subcutaneous, sublingual or intra-nasal routes.
Subcutaneous immunotherapy is the most common treatment used by allergists. Nevertheless, this method is quite expensive and requires a specialized practitioner for each injection. A major drawback of subcutaneous immunotherapy is its allergic side effects. These side effects can be either local or systemic. Groundnut allergy immunotherapies using subcutaneous route have been demonstrated to induce a high rate of adverse systemic reaction (up to 50%). Nelson et al., Treatment of anaphylactic sensitivity to peanuts by immunotherapy with injections of aqueous peanut extract, 99 J. ALLERGY CLIN. IMMUNOL. 744, 744-51 (1997); Oppenheimer et al., Treatment of peanut allergy with rush immunotherapy, 90 J. ALLERGY CLIN. IMMUNOL. 256, 256-62 (1992). Systemic side effects are caused by allergen inadvertently being injected into small subcutaneous blood vessels, or allergens diffusing into the subcutaneous blood vessels. Allergens may be transported to other organs such as the lung or distant sites of the skin, where they can provoke asthma or hives. They also may cause anaphylaxis which can result in death. Consequently, allergies with high anaphylaxis risks, such as peanut allergy, cannot be treated by subcutaneous route.
Sublingual immunotherapy was accepted by WHO as a valid alternative to the subcutaneous route and should be used in all patients who require immunotherapy and do not accept the subcutaneous route of allergen administration. However, the dose of allergen required for sublingual immunotherapy is greater than subcutaneous immunotherapy and this method sometimes induces some local adverse effects such as oral pruritus, throat irritation, swelling of tongue or throat.
Intra-nasal immunotherapy is another alternative to the subcutaneous route which has been proven to be efficient for seasonal rhinitis and asthma treatment. Hufnagl et al., Airway inflammation induced after allergic poly-sensitization can be prevented by mucosal but not by systemic administration of poly-peptides, 38 Clin. Exp. Allergy 1192, 1192-1202 (2008). Nevertheless, this route is generally not well tolerated by patients and most of them prematurely interrupt their treatment. Pajno et al., Children's compliance with allergen immunotherapy according to administration routes, 116(6) J. ALLERGY CLIN. IMMUNOL. 1380, 1380-81 (2005).
Consequently, there is a need for an immunotherapy method for groundnut allergy treatment which is safe, efficient and well tolerated by patients.